Serum Dipeptidyl Peptidase-4 Activity in Insulin Resistant Patients with Non-Alcoholic Fatty Liver Disease: A Novel Liver Disease Biomarker

Abstract

Background In a cross-sectional study we studied the fasting serum DPP-4 enzymatic activity (sDPP-4) and the insulin resistance index (HOMA2-IR) in gliptin naïve patients with type 2 diabetes and in non-alcoholic fatty liver disease (NAFLD) and in healthy controls (CNTRL).Methods and Findings sDPP-4 was measured by kinetic assay in 39 NAFLD (F/M:19/20, mean age: 47.42 yrs) and 82 type 2 diabetes (F/M:48/34, 62.8 yrs) patients and 26 (F/M:14/12, 35.3 yrs) controls. Definition of T2D group as patients with type 2 diabetes but without clinically obvious liver disease created non-overlapping study groups. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. Patients in T2D and NAFLD groups were similarly obese. 75 g CH OGTT in 39 NAFLD patients: 24-NGT, 4-IGT or IFG (“prediabetes”), 11-type 2 diabetes. HOMA2-IR: CNTRL: 1.44; T2D-group: 2.62 (p = 0.046 vs CNTRL, parametric tests); NAFLD(NGTonly): 3.23 (p = 0.0013 vs CNTRL); NAFLD(IFG/IGT/type 2 diabetes): 3.82 (p<0.001 vs CNTRL, p = 0.049 vs 2TD group). sDPP-4 activity was higher in NAFLD both with NGT (mean:33.08U/L) and abnormal glucose metabolism (30.38U/L) than in CNTRL (25.89U/L, p<0.001 and p = 0.013) or in T2D groups (23.97U/L, p<0.001 and p = 0.004). Correlations in NAFLD among sDPP-4 and ALT: r = 0.4637,p = 0.0038 and γGT: r = 0.4991,p = 0.0017 and HOMA2-IR: r = 0.5295,p = 0.0026 and among HOMA2-IR and ALT: r = 0.4340,p = 0.0147 and γGT: r = 0.4128,p = 0.0210.Conclusions The fasting serum DPP-4 activity was not increased in T2D provided that patients with liver disease were intentionally excluded. The high serum DPP-4 activities in NAFLD were correlated with liver tests but not with the fasting plasma glucose or HbA1C supporting that the excess is of hepatic origin and it might contribute to the speedup of metabolic deterioration. The correlation among γGT, ALT and serum DPP-4 activity and also between serum DPP-4 activity and HOMA2-IR in NAFLD strongly suggests that serum DPP-4 activity should be considered as a novel liver disease biomarker.

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

“…Researchers speculated that these discrepancies in diabetic patients may be due to factors such as disease duration, patient age and glycemic control. In patients with NAFLD, we found that hepatic DPP4 expression was negatively correlated with HOMA-IR, which was inconsistent with that of a previous report showing a positive correlation between serum DPP4 activity and HOMA2-IR in NAFLD patients (20). Firneisz et al (20) also showed that DPP4 activity in NAFLD patients with glucose intolerance was lower than that in NAFLD patients with normal glucose tolerance, complicating the role of IR in DPP4 activity in NAFLD.…”

“…Indeed, DPP4 activity was greater in NAFLD patients than in control subjects and patients with T2DM, and DPP4 activity was correlated with HOMA2-IR (20). Serum DPP4 activity was significantly higher in NASH patients than in control subjects and was correlated with the histopathological grade of liver disease.…”

Persons with latent autoimmune diabetes in adults express higher dipeptidyl peptidase-4 activity compared to persons with type 2 and type 1 diabetes

“…Our third finding is partially in accordance with the study of Firneisz et al [26] (2010) who determined serum DPP4 activity at fasting sate and after test meal in 41 persons with T1DM, 87 with T2DM accompanied with prominent insulin resistance (IR) and in 25 healthy volunteers.…”

“…We could explain this with the fact that AI diabetes is a T-cell mediated organspecific disease, initiated by the imbalance between pathogenic and regulatory T-lymphocytes. DPP-4 is the lymphocyte cell surface protein CD26, critical in T-cell biology as a marker of Tcell activation [24,26]. DPP-4 inhibition increased regulatory T-cells and reversed recent-onset diabetes in a non-obese mouse model of AI diabetes [27].…”

The role of endothelial dysfunction driven by adipocitokines in the development and progression of microvascular complications in patients with type 1 and type 2 diabetes

“…In animal and cell culture studies adiponectin increased the bioavailability of NO directly, stimulating eNOS, and indirectly, by reducing the concentration of superoxide products (27)(28)(29). Sharma et al (2008) The results of recent experimental studies suggest an increased expression of DPP-4 in adipocytes of visceral fat and increased serum enzymes in patients with IR and T2DM (39,40). In vitro studies also suggest a possible link between DPP4 activity and renovascular protective effect (41,42).…”